Insect repellents



Patented Feb. 3, 1953 INSECT REPELLENTS Nathan L. Drake, College Heights, Md., Wilbur .L Shenk, Cleveland, Ohio, and Charles M. Eaker, Alton, Mo., assignors to the United States of America as represented by the Secretary of the UNITEo STAT Army No Drawing. Application January 11, 1949, Serial No. 70,396

6 Claims.

This invention relates to insect repell-ents. We have discovered that the application of a nionoamide ester of a dibasic acid whose hydroeen atoms in the carboxyl and amido `group are n. ESTERS OF N,NSUBSTITUTED SUCCINAMIC ACID (SUCCINIG ACID MONOAMIDE) Repellency on Application to Skin replaced by hydrocarbon residues, when applied 5 i lllfsleliref to the hernan skin or a fabric effectively repels Mmmm] Anopheles Fabric saiust insects, particularly Ades aegypti `and Anopheles ,QZ qadfi- Aedes aggym'z quadrimaculatus. maman rlests to measure the repellency of the abovey. Alma I Vms.` mentwned compounds aealnst msets by SL-m apsrssiahyi.; @the amm 274 4s over m (uw. plication were conducted by smearing the corn- N,Ndithy1; I1pr py1 322 76 De pound on the arms of test personnel, who then N eethy1 ;i.pmpy1 esten 255 72 DI, thrust their arms into cages containing insects. Nyl-{iithyli sbuiyl 377 50 D0- y The arms were exposed for Sil-minute intervals Nelsqimpmpyl.;pmpyl 215 37 at 3 minutes each until the rst msectblte.` 15 NCliifmpmpykSecbutyl 318 41 over, days' Tests to measure the repellency of fabrics nn- @stelpregnated with the above-mentioned compounds Nfe'ef'-PTOPW? n'fopyl 341 33 DO- against insects were conducted by uniformly im- N,N iipr0py1 i-propyi 31o 3o Do. pregnating mercerized cotton h-ose with the com- Nliiwmpyk Swbutyl 257 64 DQ. pound at a rate equlvalent to 3.3 gms. per sq. ft., e er, drawing the dried hose over the arms of test per- Nixltethylene; 255 72 At least 1 dey. sonnel, who then thr-ust their covered arms into N,N-pentamthy1ene; 193 ."4 cages containing insects for 1 to 2 minutes. i'ropyl este Examples of diibasic amido acids whose hydrov carbon-substituted monoamicle esters have insect b' ESTERS AgiUflgggAD/?MIG ACQ) repellent properties are :for instance, succinarnic acid, maleami-c acid, glutaramic acid., adipamic N,Ndiethy1;ethylester... 201 51 over 10 days4 acid; the substituent hydrocarbon resid-ues on Nlfmethylem? 268 35 either end of the molecule may for instance be methyl, ethyl, n-propyl, i-propyl, sec-butyl, ,pen-

n. Es'rERs or N,NsUBsTITUTED GLUTARAMIC ACID tamethylene (on the nitrogen of the amido (GLUTARIG ACID MONOAMIDE) group), etc.

Thus, the esters contemplated by the present bgrgdiethyl-:mthyi estera 00 47 over 10 days. invention have the general formula' klgf'n'pmpyl'; methyl 30 39 'DO' Nybtdiqi-propyb; ethyl 26B 40 Do. 'D 9S el. l RZNCO Cnam COO NNtei-i-propyr; msthy1 248` 39 i no.

eS el'. wherein R and R are hydrocarbon residues not Ntlh-l-propyr; any1 289 37 no, necessarily the same, wherein n is an integer of N,Ndipropy1; n propyi 244 36 Do. at least 2, and wherein is 1 or 2. ester The following table illustrates the results lobtained by the above test method-s against Aedes aegypti and Anopheles quadrimocuiatus, as` examples of inse-cts against which the invention is applicable, by using compounds in accordance with the present invention:

d. EsTERs 0F Niv-scesi* (ADIPIC ACID MONOAMIDE) ate product is the isopropyl monoester of sucoinic acid, of which 163 gms. are obtained in the form of a solid having a, melting point of 49-51" C.; its boiling point is 92-94 C. at .3 mm. pressure.

The above intermediate compound is converted A. Dibasic-acid anhydride -lsecondary amine N ,N-di-substituted dibasic acid amide.

benzene alcohol toluenesulfonic acid CH2.COOR S0012 B. Dibasic-acid anhydride -lalcohol ester of N,Ndisubstituted dibasic acid amide.

CH2-COOR CH2.COCH

The following examples illustrate the preparation of several typical insect repellent compounds enumerated in the above table:

Example 1 90 gms. of succinic anhydride are placed in 600 cc. of dry benzene and cooledin an ice bath. 98 cc. of diethylamine in 'l0 cc. of benzene are heated slowly by stirring. Thereafter the reaction mixture is heated under reflux and in a steam bath for about 4 hours. The yield is 153 gms. of N,Ndiethyl succinamic acid.

30 gms. of N,Ndiethyl succinamic acid obtained by the foregoing reaction are reacted with 25 gms. of ethyl alcohol in the presence of 90 gms. of benzene and 1.29 gms. of toluenesulfonic acid catalyst. Heating and reiluxing the reaction mixture near the boiling point of benzene for 6 hours yields 22 gms. of the ethyl ester of N,N diethyl succinamic acid, a liquid boiling at 10G-107 C. at 1 mm. pressure, and whose refractive index is nD215=1.4509.

Example 2 55 gms. of diethylamine in 35 gms. of ether are reacted with 54 gms. of succinic acid chloride n-propyl ester in 35 gms. of ether at about 10 C. The reaction mixture is permitted to stand at that temperature for two days. 44 gms. of npropyl ester of N,Ndiethyl succinamic acid are obtained; a liquid having a boiling point of 10S-104 C. at .3 mm. pressure.

Example 3 30 gms. of N,Ndiethyl succinamic acid are reacted with 25 gms. of isopropyl alcohol in the presence of 90 gms. of benzene and 1.5 gms. toluenesulfonic acid catalyst. 14 gms. of the isopropyl ester of N,Ndiethyl succinamic acid are obtained in the form of a liquid having a boiling point of 98-99 C. at .5 mm. pressure, and whose refractive index is upm-:1448.

Example 4 36 gms. of succinic acid chloride n-propyl monoester in `20 gms. of dry ethyl ether are added to 65 gms. of 20% potassium hydroxide, 15 gms. of dry ethyl ether and 21 gms. of di-n-propylamine. The reaction mixture is permitted to stand at about C. for about 2 days. 39 gms. of the n-propyl ester of N,Ndinpropyl succinamic acid are obtained.

Example 5 200 gms. of succinic acid anhydride and 124 gms. of isopropanol are heated in a steam cone for 16 hours. The reaction product is filtered, poured into 2 liters of 10% sodium carbonate solution, Washed with ethyl ether, acidified with syrupy phosphoric acid, extracted with ethyl ether, a little benzene added, shaken with magnesium sulfate, and distilled. The resulting intermediinto the succinic acid chloride isopropyl monoester by adding gms. of succinic acid monoisopropyl ester to 150 gms. of puried thionyl chloride in 75 gms. of dry chloroform. The reaction mixture is permitted to stand overnight, then warmed to about 50 C. for about 30 minutes, and the excess thionyl chloride is removed under reduced pressure. 111 gms. of succinic acid chloride isopropyl monoester are obtained.

35 gms. of the succinic acid chloride isopropyl monoester in 25 gms. of ethyl ether are then added to 66 gms. of 20% potassium hydroxide and 25 gms. of piperidine in 20 gms. of ethyl ether at 0 C. with vigorous stirring. The resulting reaction product is the isopropyl ester of N,Npentamethylene succinamic acid; the yield is 30 gms. of a liquid whose boiling point is 115-116 C. at .4 mm. pressure; refractive index is nD21-5=1.4730.

Emample 6 To a cold solution of 44 gms, (.6 mol) diethylamine in 90 ml. absolute ether are added 31 gms. (.22 mol) maleic acid chloride ethyl monoester in 40 gms. absolute ether with cooling and stirring. After all the chloride has been added, the mixture is allowed to stand overnight at room temperature without stirring.

The amine hydrochloride is removed by filtration and the ether solution is washed with 5% phosphoric acid (cold) twice with cold saturated sodium chloride solution. The ether solution is dried over magnesium sulfate. The sulfate is removed by filtration,

The ether is removed by distillation and the ester distils at 115-116 at a pressure of 1 mm.

The yield is 22 gms. of N,Ndiethy1 maleamic acid ethyl ester, 50% of theory.

It is a water-insoluble liquid; refractive in- To a cold solution of 51 gms. (.6 mol) piperidine in 90 ml. absolute ether are added 31 gms. (.22 mol) maleic acid chloride ethyl monoester in 40 gms. absolute ether with cooling and stirring. This ester is then treated as the one in 5 Example 6.

The ester distils at 137-138 C. at a pressure of 1 mm. The yield was 14 gms. of N,Npen`ta methylene maleamic acid ethyl ester; 30.5% of theory.

It is a Water-insoluble liquid refractive index:

44 gms. of glutaric acid methyl ester monochloride are reacted with 42 gms. (60 ml.) diethylamine in the presence of 70 m1. of dry ether. The yield is 40 gms. of the methyl ester of N,N diethyl glutaramic acid, a Water soluble liquid Whose boiling point is 1D0-101 C. at .4 mm. pres- Whose refractive index is nD21-9=1.4560.

Example 9 Io 48 gms. of 25% potassium hydroxide and 22.2 gms. of di-isopropylamine are added 36 gms. of adipic acid chloride methyl monester in 30 ml. of ether at 0 C. After all the monoester has been added, the solution is stirred for 30 minutes,

additional ether is added, and the formed aqueous layer i-s separated. The ether layer is then Washed with 5% cooled phosphoric acid solution,

and the excess acid solution is removed by washl ing with cold salt solution. The ether is then dried, and the solution filtered. Finally, the ether is removed by distillation, and the ester remains, which distills at 110-111 C. at .5 mm. pressure. The yield is 29 gms. of the methyl ester of N,N zii-isopropyl adipamic acid, a Water-White liquid Whose refractive index is upm-9:14560.

acid, and a non-toxic insect-repellent-adjuvant as a carrier therefor.

2. An insect repellent composition comprising the propyl ester of N,Ndiethyl succinamic acid and a non-toxic insect-repellent-adjuvant as a carrier therefor.

3. An insect repellent composition comprising the n-propyl ester of N,Ndiethyl succinamic acid and a non-toxic insect-repellent-adjuvant as a carrier therefor.

4. An insect repellent composition comprising the propyl ester of N,Npentamethylene suc cinamic acid, and a non-toxic insect-repellent-adjuvant as a carrier therefor.

5. The process of preparing an N,Nhydrocar bon-substituted dibasic acid monoamide alkyl ester, comprising reacting a member of the group consisting of dibasic acids and dibasic acid anhydrides with an N,Nhydrocarbon-substituted secondary amine, and reacting the reaction product with a monohydric alcohol.

6. The process of preparing an N,Nhydrocar bon-substituted dibasic acid monoamide alkyl ester, comprising reacting a member of the group consisting of dibasic acids and dibasic acid anhydrides with an N,N-hydrocarbonsubstituted secondary amine, and reacting the reaction product with a monohydric alcohol in the presence of benzene and toluene sulfonic acid as a catalyst.

NATHAN L. DRAKE. WILBUR J. Sli-ENK. CHARLES M. EAKER.

REFERENCES CITED The following references are of record in the le of this patent:

UNITED STATES PATENTS Number Name Date 2,306,095 Valjavec Dec. 22, 1942 2,313,573 Orthner Mar. 9, 1943 2,400,006 Jones et al May '7, 1946 2,502,478 Padbury Apr. 4, 1950 OTHER REFERENCES OSRD, Bimonthly Progress Report Number 21, Sec. 1, December 31, 1944. Page 10, Orlando Number 0-6166 Ethyl N,Ndiethylsuccinamate.

OSRD, Bimonthly Progress Report Number 24, Sec. 1, June 30, 1945. Pages 2, 3, Orlando Nos. 0-6484, 0-6511; resp. adipamic acid, N,N`diso prop1y, methyl ester, and adipamic acid, N.N diethy1, ethyl ester.

OSRD, Bimonthly Progress Report No. 25, Sec. 1, August 31, 1945. Page 12, Orlando No. 0-6484.

Linduska et al., Flea Repellents, volume 41, 1947, Chemical Abstracts, page 3580. 

1. AN INSECT REPELLENT COMPOSITION COMPRISING A MEMBER OF THE GROUP CONSISTING OF THE PROPYL ESTER OF N,N-DIETHYL SUCCINAMIC ACID AND THE PROPYL ESTER OF N,N-PENTAMETHYLENE-SUCCINAMIC ACID, AND A NON-TOXIC INSECT-REPELLENT-ADJUVANT AS A CARRIER THEREFOR. 